Mark Shapiro

Drug-Related Pneumonitis in Patients With Advanced Renal Cell Carcinoma Treated With Temsirolimus

PURPOSE Pneumonitis has occurred in patients treated with inhibitors of the mammalian target of rapamycin (mTOR). In a phase III study of patients with previously untreated, poor-prognosis, advanced renal cell carcinoma (ARCC), the mTOR inhibitor temsirolimus improved survival compared with interferon. We performed a retrospective, independent, blinded radiographic review of chest computed tomography (CT) images of patients in this study to characterize temsirolimus-related pneumonitis. PATIENTS AND METHODS Patients were treated with intravenous temsirolimus 25 mg once weekly or subcutaneous interferon alfa 3 million units, with an increase to 18 million units, thrice weekly. Drug-related pneumonitis was identified based on sequential chest CT images, required every 8 weeks, showing changes consistent with pneumonitis and not pneumonia (infection) or disease progression as correlated with clinical data. Cumulative probability of drug-related pneumonitis was estimated using the Kaplan-Meier method. RESULTS Eight (6%) of 138 and 52 (29%) of 178 evaluable patients on interferon and temsirolimus treatment, respectively, developed radiographically identified drug-related pneumonitis. Time to onset of pneumonitis was significantly shorter on the temsirolimus arm than on the interferon arm (log-rank P < .001). Estimated cumulative probability of pneumonitis at 8 and 16 weeks from first dose was 21% and 31%, respectively, on the temsirolimus arm and 6% and 8%, respectively, on the interferon arm. Respiratory symptoms were observed around time of onset of radiographically diagnosed temsirolimus-related pneumonitis in 16 (31%) of 52 patients. CONCLUSION Patients with ARCC receiving temsirolimus should be monitored closely for development of pneumonitis, and their management should be altered if clinical symptoms appear.

Long‐term efficacy and safety of bosutinib in patients with advanced leukemia following resistance/intolerance to imatinib and other tyrosine kinase inhibitors

Long‐term efficacy and safety of bosutinib (≥4 years follow‐up from last enrolled patient) were evaluated in an ongoing phase 1/2 study in the advanced leukemia cohort with prior treatment failure (accelerated‐phase [AP, n = 79] chronic myeloid leukemia [CML], blast‐phase [BP, n = 64] CML, acute lymphoblastic leukemia [ALL, n = 24]). Fourteen AP, 2 BP, and 1 ALL patient remained on bosutinib at 4 years (vs. 38, 8, 1 at 1 year); median (range) treatment durations: 10.2 (0.1–88.6), 2.8 (0.03–55.9), 0.97 (0.3–89.2) months. Among AP and BP patients, 57% and 28% newly attained or maintained baseline overall hematologic response (OHR); 40% and 37% attained/maintained major cytogenetic response (MCyR) by 4 years (most by 12 months). In responders at 1 versus 4 years, Kaplan‐Meier (KM) probabilities of maintaining OHR were 78% versus 49% (AP) and 28% versus 19% (BP); KM probabilities of maintaining MCyR were 65% versus 49% (AP) and 21% versus 21% (BP). Most common AEs (AP, BP) were gastrointestinal (96%; 83%), primarily diarrhea (85%; 64%), which was typically low grade (maximum grade 1/2: 81%; 59%) and transient; no patient discontinued due to diarrhea. Serious AEs occurred in 44 (56%) AP and 37 (58%) BP patients, most commonly pneumonia (n = 9) for AP and pyrexia (n = 6) for BP; 11 and 13 died within 30 days of last dose (2 considered bosutinib‐related [AP] per investigator). Responses were durable in ∼50% AP responders at 4 years (∼25% BP patients responded at year 1, suggesting possible bridge‐to‐transplant role in BP patients); toxicity was manageable.Am. J. Hematol. 90:755–768, 2015.

Factors influencing long-term efficacy and tolerability of bosutinib in chronic phase chronic myeloid leukaemia resistant or intolerant to imatinib

The dual SRC/ABL1 tyrosine kinase inhibitor bosutinib is indicated for adults with Ph+ chronic myeloid leukaemia (CML) resistant/intolerant to prior therapy. This analysis of an ongoing phase 1/2 study (NCT00261846) assessed effects of baseline patient characteristics on long‐term efficacy and safety of bosutinib 500 mg/day in adults with imatinib (IM)‐resistant (IM‐R; n = 196)/IM‐intolerant (IM‐I; n = 90) chronic phase (CP) CML. Median treatment duration was 24·8 months (median follow‐up, 43·6 months). Cumulative major cytogenetic response (MCyR) rate [95% confidence interval (CI)], was 59% (53–65%); Kaplan‐Meier (KM) probability of maintaining MCyR at 4 years was 75% (66–81%). Cumulative incidence of on‐treatment progression/death at 4 years was 19% (95% CI, 15–24%); KM 2‐year overall survival was 91% (87–94%). Significant baseline predictors of both MCyR and complete cytogenetic response (newly attained/maintained from baseline) at 3 and 6 months included prior IM cytogenetic response, baseline MCyR, prior interferon therapy and <6 months duration from diagnosis to IM treatment initiation and no interferon treatment before IM. The most common adverse event (AE) was diarrhoea (86%). Baseline bosutinib‐sensitive BCR‐ABL1 mutation was the only significant predictor of grade 3/4 diarrhoea; no significant predictors were identified for liver‐related AEs. Bosutinib demonstrates durable efficacy and manageable toxicity in IM‐R/IM‐I CP‐CML patients.

Long-term evaluation of cardiac and vascular toxicity in patients with Philadelphia chromosome-positive leukemias treated with bosutinib

Vascular and cardiac safety during tyrosine kinase inhibitor (TKI) therapy is an emerging issue. We evaluated vascular/cardiac toxicities associated with long‐term bosutinib treatment for Philadelphia chromosome‐positive (Ph+) leukemia based on treatment‐emergent adverse events (TEAEs) and changes in QTc intervals and ejection fraction in two studies: a phase 1/2 study of second‐/third‐/fourth‐line bosutinib for Ph+ leukemia resistant/intolerant to prior TKIs (N = 570) and a phase 3 study of first‐line bosutinib (n = 248) versus imatinib (n = 251) in chronic phase chronic myeloid leukemia. Follow‐up time was ≥48 months (both studies). Incidences of vascular/cardiac TEAEs in bosutinib‐treated patients were 7%/10% overall with similar incidences observed with first‐line bosutinib (5%/8%) and imatinib (4%/6%). Few patients had grade ≥3 vascular/cardiac events (4%/4%) and no individual TEAE occurred in >2% of bosutinib patients. Exposure‐adjusted vascular/cardiac TEAE rates (patients with events/patient‐year) were low for second‐line or later bosutinib (0.037/0.050) and not significantly different between first‐line bosutinib (0.015/0.024) and imatinib (0.011/0.017; P ≥ 0.267). Vascular/cardiac events were managed mainly with concomitant medications (39%/44%), bosutinib treatment interruptions (18%/21%), or dose reductions (4%/8%); discontinuations due to these events were rare (0.7%/1.0%). Based on logistic regression modelling, performance status >0 and history of vascular or cardiac disorders were prognostic of vascular/cardiac events in relapsed/refractory patients; hyperlipidemia/hypercholesterolemia and older age were prognostic of cardiac events. In newly diagnosed patients, older age was prognostic of vascular/cardiac events; history of diabetes was prognostic of vascular events. Incidences of vascular and cardiac events were low with bosutinib in the first‐line and relapsed/refractory settings following long‐term treatment in patients with Ph+ leukemia. Am. J. Hematol. 91:606–616, 2016.

Real-world Analysis of Tyrosine Kinase Inhibitor Treatment Patterns Among Patients With Chronic Myeloid Leukemia in the United States

PURPOSE The treatment of chronic myeloid leukemia (CML) has improved considerably since the introduction of the tyrosine kinase inhibitor (TKI) imatinib in 2001 and the approval of second-generation TKIs (dasatinib and nilotinib) beginning in 2006.The objective of this study was to explore treatment patterns of TKI therapy (adherence, duration, and switching) among patients with CML in the United States, following the availability of second-generation TKIs. METHODS This study used US health plan claims data from January 1, 2007, through December 31, 2011. Patients were required to be aged ≥18 years, have a prescription fill for a TKI, and a diagnosis of CML. Duration of TKI use was determined based on a gap in TKI coverage of ≥180 consecutive days after TKI initiation or switch to another TKI within the 180-day window. To account for censoring due to disenrollment from the health plan or end of the study period, median treatment duration was projected by using the Kaplan-Meier estimator. FINDINGS We identified 695 patients who started TKI treatment and had a CML diagnosis during the study time frame. The mean age of patients was 55 years, and 58% of patients were male. The most common first-line TKI was imatinib (82%), with dasatinib and nilotinib use equally distributed (9%). Among the 148 (21.3%) patients who initiated a second-line TKI, the majority had switched from imatinib to dasatinib or nilotinib (86%). The median duration of first-line TKI use was 39.8 months and second-line TKI use was 22.4 months. Median duration of treatment for first-line (P = 0.4342) and second-line (P = 0.1792) treatment did not differ significantly according to TKI. Mean adherence (ie, proportion of days covered) during the first line of therapy was 0.90. IMPLICATIONS For the US patients studied, we found that imatinib was used more frequently than other TKIs in the first-line setting, but there was an increased use of second-generation TKIs in the first-line setting over time (9% in 2008 vs 43% in 2011 were nilotinib or dasatinib users). Only about one fifth of patients switched to a second-line TKI during the period of data collection.

Health-related quality of life during bosutinib (SKI-606) therapy in patients with advanced chronic myeloid leukemia after imatinib failure

Abstract Objectives: The tyrosine kinase inhibitor (TKI) bosutinib has demonstrated activity in patients with advanced phase chronic myeloid leukemia (CML), but effects on health-related quality of life (HRQoL) remain unexplored. This study evaluated HRQoL in advanced CML patients receiving bosutinib in an ongoing phase 2 study following resistance or intolerance to prior imatinib therapy. Methods: This analysis included data from 76 accelerated-phase (AP) and 64 blast-phase (BP) patients resistant/intolerant to prior imatinib with or without prior exposure to other TKIs. Patient-reported HRQoL assessments completed at baseline; weeks 4, 8, and 12; every 12 weeks thereafter; and at treatment completion included the Functional Assessment of Cancer Therapy–Leukemia (FACT-Leu); general health status was assessed using the 5-item EuroQol (EQ-5D) instrument and a visual analog scale (VAS). Results: HRQoL at baseline was somewhat worse in BP versus AP CML patients. There was a significant improvement in the mean FACT-Leu Total scale at weeks 24, 36, and 48 in AP CML patients and at weeks 4, 8, 12, 24, 36, 48, and 96 in BP CML patients compared with baseline. EQ-5D Utility scores were stable throughout treatment in AP CML patients but significantly improved versus baseline in BP CML patients at weeks 4, 8, 12, and 36. Mean VAS scores were significantly improved at weeks 8, 36, and 48 in AP CML patients and at weeks 4, 8, 12, 24, 36, and 96 in BP CML patients. The lack of a comparison group limits attribution of improvements in HRQoL specifically to bosutinib treatment; potential bias due to non-ignorable dropout may limit the ability to generalize these findings to situations where durations of therapy exceed the 96-week follow-up duration of the present study. Conclusion: These findings suggest that bosutinib therapy is associated with improved HRQoL in advanced phase CML patients. Clinical trial registration: NCT00261846.

Acute myeloid leukemia: a retrospective claims analysis of resource utilization and expenditures for newly diagnosed patients from first-line induction to remission and relapse

Abstract Objective: The objective of this study was to estimate resource utilization and expenditures for patients with acute myeloid leukemia (AML) in a real-world claims database. Research design and methods: AML patients were identified in MarketScan claims databases between 1 January 2009 and 31 January 2015. Patients had a minimum of two AML diagnosis codes, hospitalization within 14 days after initial diagnosis, and ≥6 months of enrollment before initial diagnosis. Patients were monitored from first-line induction to a record of remission. A subset had a record of a second treatment period, defined as time from relapse to remission. Patient demographics, AML risk factors, and comorbidities were recorded. Descriptive analysis of utilization and expenditures (in 2014

Safety and efficacy of second-line bosutinib for chronic phase chronic myeloid leukemia over a five-year period: final results of a phase I/II study

US) were reported for each cohort. Results: The inclusion criteria were met in 1597 patients (mean age, 58.4 years; 51.0% male). Ninety percent of patients had ≥1 risk factor for AML. Mean (SD) healthcare expenditures for patients from first-line induction to remission (n = 681) were

Long‐term patient‐reported outcomes from an open‐label safety and efficacy study of bosutinib in Philadelphia chromosome–positive chronic myeloid leukemia patients resistant or intolerant to prior therapy

208,857 (

Assessment of Early Molecular Response As a Predictor of Long-Term Clinical Outcomes in the Phase 3 BELA Study

152,090). Of the 157 who had a record of relapse, 70 had a record of a second remission. Expenditures for these patients (n = 70) from relapse to remission were